Okayasu I, Hatakeyama S, Yoshida T, Yoshimatsu S, Tsuruta. K, Miyamoto H, Kimura Y: ... Khan KN, Nakata K, Kusumoto Y, Shima M, Ishii N, Koji T,. Nagataki S: ...
Digestive Diseases and Sciences, Vol. 43, No. 2 (February 1998), pp. 317± 322
Hepatic Perfusion Changes After Transcatheter Arterial Embolization (TAE) of Hepatocellular Carcinoma Measurement by Dynamic Computed Tomography (CT) YOSHITO TSUSHIMA, MD, YASUSHI UNNO, RT, JUN KOIZ UMI, MD, and SHOICHI KUSANO, MD
We observe d the hemodynamic change s at the leve l of the he patic pare nchyma induce d by transcathe te r arterial embolization (TAE) for hepatoce llular carcinoma in 22 patie nts. TAE was pe rforme d by administration of a mixture of iodize d oil, adriamycin, and mitomycin C, followe d by inje ction of gelatin sponge particle s (1-mm pieces). Pe rfusion measure ments (arte rial and portal) were done by dynamic compute d tomography (CT). Arterial pe rfusion was incre ase d two to six days afte r TAE (0.146 6 0.073 ml/min/m l, P , 0.0002) compare d with that before TAE (0.064 6 0.039) , but de crease d again one month afte r TAE (0.086 6 0.038) . Portal perfusion was de crease d two to six days afte r TAE (0.541 6 0.180, P , 0.001) compare d with that be fore TAE (0.733 6 0.263) and was grossly unchange d one month after TAE (0.651 6 0.214) . We suspe cted that the se pe rfusion change s were due to acute in¯ ammatory re sponse s. Quanti® cation of tissue perfusion by dynamic CT was use ful for studying he modynam ic change s afte r TAE. KEY WORDS: live r perfusion; compute d tomography; transcathete r arterial embolization.
Transcathe ter arterial embolization (TAE) is a therape utic te chnique for the treatment of patie nts with he patoce llular carcinom a (HCC). Usually, a mixture of anticance r age nts and iodize d oil (Lipiodol) is administe red into the hepatic arte ry, followe d by injection of gelatin sponge particle s (1± 6). Se ve ral inve stigators have asse sse d he modynam ic change s at the le ve ls of the portal trunk and prope r he patic arte ry afte r TAE by using Dopple r ultrasonograp hy (7, 8) . O hnishi e t al ( 8) re porte d that portal ve nous ¯ ow at the portal trunk was incre ase d Manuscript received April 7, 1997; accepted October 15, 1997. From the De partme nt of Radiology, National De fense Me dical College , 3-2 Namiki, Tokorozawa, Saitama, Japan. Address for re print re quests: Dr. Yoshito Tsushima, De partme nt of Radiology, National De fense Me dical College , 3-2 Namiki, Tokorozawa, Saitama, Japan.
on the ne xt day afte r TAE and that it re maine d incre ase d for at le ast two we e ks. Taoure l e t al ( 7) e valuate d he patic arte ry and portal ve nous ¯ ow with color and duple x Dopple r sonogra phy be fore and afte r TAE and conclud e d that occlusion of he patic arte ry by TAE was rapidly re canaliz e d or re sorbe d and that change s in the he patic arte rial pe rfusion did not alte r portal ve nous ¯ ow. Howe ve r, to our knowle dge , the change s in arte rial and portal pe rfusion at the he patic pare nchym al le ve l have not be e n pre viously de scribe d. The purpose s of this study were to e valuate the alte ration in arte rial and portal pe rfusion of the hepatic pare nchyma afte r TAE using dynamic CT and to obse rve the he modynam ic change s induce d by TAE.
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Digestive Diseases and Sciences, Vol. 43, No. 2 (February 1998) 0163-2116/98/0200-0317$15.00/0 Ñ
1998 Plenum Publishing Corporation
TSUSHIMA E T AL TABLE 1. S UMMARY
OF
B ACKGROUND
OF
HCC P ATIENTS*
Sex Male Female Age (yr) Range Mean 6 SD Cause of disease HBV HCV NBNC Child’s classi® cation A B C
13 9 52 ± 76 66.14 6 6.82 3 16 3 17 4 1
* N 5 22. HBV : hepatitis B virus; HCV: he patitis C virus; NBNC nonB, nonC he patitis.
MATERIALS AND METHODS Subjects. Twenty-two consecutive patie nts were prospective ly included in this study. All patie nts had HCC associate d with liver cirrhosis. The diagnosis of liver cirrhosis was based on histologic ® ndings and/or conventional liver function test (me asureme nt of serum glutamic oxaloace tic transaminase, glutamic pyruvic transaminase, albumin, gamma globulin, total bilirubin, cholineste rase, and platelet count). The diagnosis of HCC was made by needle biopsy or based on a combination of e levate d serum a -fetoprotein leve l and characteristic ® ndings of CT, ultrasonography, and angiography. Sixtee n patients we re untreate d and six has undergone previous TAE. Informed consent was obtaine d from all patie nts. The background of the patients was summarized in Table 1. Angiogr ap hy an d TAE. After an ove rnight fast, celiac and superior me sente ric angiography was performed. No portal thrombus was observe d angiographically in any of the cases. TAE was performed by administration of a mixture of 2± 8 ml of iodized oil (Lipiodol Ultra-Fluid; Laboratoire Guerbet, France), 10 ± 20 mg of adriamycin, and 4 ± 10 mg of mitomycin C, followed by injection of ge latin sponge particles (Ge lfoam; Upjohn, Tokyo), cut into 1-mm pieces, via the proper hepatic artery (PHA; N 5 11) , right hepatic artery (RHA; N 5 9), or ante rior branch of the right hepatic arte ry (AHA; N 5 2). The amount of injected gelatin sponge was adjusted according to the size of the tumor and its vascularization at angiography, and the e ntire PHA, RHA, or AHA ¯ ow was interrupted a fe w centimeters beyond its origin. Perfu sion Measu rem ents. Perfusion me asureme nts of the hepatic parenchyma we re carried out within one we ek before TAE (all patie nts), once betwe en two and six days afte r TAE (all patients), and about one month afte r TAE (10 patie nts). Afte r an overnight fast, single-location dynamic sequences were performed. A ® xed 10-mm-thick slice, which was selected to include the right hepatic lobe, splee n, and portal trunk, was repeate dly scanned. Scanning was performed using a Somatom Plus scanner (Sieme ns Asahi Medi-Tech, Tokyo, Japan) with a 1-sec scanning time at 0 sec and at 7, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 38, 45, 52, 59, 66, 73, 80, and 87 sec afte r the injection of contrast mate rial. A bolus infusion of 40 ml of nonionic
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contrast mate rial (ioversol 320 mg/ml; Optiray, Yamanouchi, Tokyo) was given at 5 ml/sec via a 20-gauge intrave nous cathe te r in the antecubital fossa. Patie nts were asked to hold their breath at 0 sec, for about 30 sec at 7± 31 sec, and the n for each scanning at 38 ± 87 sec. Re gions of intere st (RO Is) of pare nchym a we re made as large as possible to allow for re gional variations in the right he patic lobe and splee n. V e ssels we re not included in RO Is and the he patic parenchym a involve d by HCC was e xcluded. RO Is we re also drawn within the aorta and portal trunk. Time -atte nuation curves we re made for the se are as, and arte rial and portal pe rfusion of the hepatic pare nchyma we re calculate d based on the me thods de scribed by Miles and coworkers (9, 10) and B lomley e t al ( 11) , as below. Hepatic arte rial perfusion per volume was calculated by dividing the peak gradient of the liver time -atte nuation curve prior to the peak splenic atte nuation (preportal phase) by the peak aortic CT number increase , since portal perfusion is negligible during the preportal phase. This value expresses perfusion as milliliters per second per milliliter and was multiplied by 60. The arte rial component of the liver time -atte nuation curve was the n remove d from the raw time -atte nuation curve of the liver in the following manne r. Dividing the preportal liver gradient by the peak splenic gradient gives a me asure of the ratio of hepatic arterial to splenic perfusion. Therefore, the arte rial time atte nuation curve of the liver was obtained by scaling the time-atte nuation curve of the splee n by this ratio. This scaled curve represents the liver time-atte nuation curve if the re is no portal ve nous in¯ ow, assuming that the transit times through the liver are similar to that of the splee n and that arrival times of arterial blood in the spleen and liver are similar. This arte rial curve of the liver was subtracted from the raw time -atte nuation curve of the liver. This subtracted time -atte nuation curve e xpresses the parenchymal e nhancement due to portal ¯ ow. Therefore, portal perfusion per volume was calculated by dividing the peak gradient of this curve afte r the time of peak splenic atte nuation by the peak portal trunk CT number increase . Data Analysis. Pe rfusion was expressed as the mean 6 standard deviation ( SD ). The rate of perfusion change was calculated as follows: perfusion two to six days afte r TAE/ perfusion before TAE. The two-tailed Student’ s t te st with Bonferroni correction was used for statistical analysis, and P , 0.05 was considered signi® cant.
RESULTS Neither portal ve in invasion nor arterioportal shunt was obse rve d on angiography, and TAE was successfully performe d in all patie nts. Change s in arte rial and portal pe rfusion of the hepatic pare nchyma are shown in Figure s 1 and 2. In one case , portal pe rfusion ® ve days afte r TAE could not be calculate d because of respiratory artifact. Arterial pe rfusion in the right he patic lobe was signi® cantly increase d two to six days afte r TAE (0.146 6 0.073 ml/min/m l; P , 0.0002), compare d Digestive Diseases and Sciences, Vol. 43, No. 2 (February 1998)
PERFUSION CHANGES DUE TO TAE
Fig 1. Change s in the he patic arte rial perfusion. Arterial pe rfusion was increase d two to six days afte r TAE compared with that be fore TAE, but de creased again one month afte r TAE.
with that be fore TAE (0.064 6 0.039 ml/min/ml) , and de crease d again one month afte r TAE (0.086 6 0.038 ml/min/m l; P , 0.02) . An incre ase in arte rial pe rfusion was obse rve d two to six days afte r TAE in 20 of 22 patie nts, and a slight decrease was se en in two patie nts. The rate of arterial pe rfusion change was 2.970 6 1.874, and the re was no statistical diffe rence in the rate be twee n patie nts who had pre viously unde rgone TAE and those who were pre viously untre ated (3.164 6 1.710 vs 2.897 6 1.980) . Portal perfusion in the right he patic lobe was signi® cantly de cre ase d two to six days afte r TAE (0.541 6 0.180 ml/min/ml; P , 0.001) compare d with that be fore TAE (0.733 6 0.263 ml/min/ml) but grossly unchange d one month afte r TAE (0.651 6 0.214 ml/min/ml) . This decrease in portal perfusion was obse rve d two to six days afte r TAE in 18 of 21 patie nts, and a slight increase was se en in thre e patie nts. The rate of portal pe rfusion change was 0.775 6 0.250, and the re was no statistical diffe rence in the rate be twee n patie nts who had pre viously unde rgone TAE and those who were pre viously untre ated (0.825 6 0.286 vs 0.760 6 0.245) . Digestive Diseases and Sciences, Vol. 43, No. 2 (February 1998)
Fig 2. Change s in the hepatic portal perfusion. Portal perfusion was decrease d two to six days after TAE , compared with that be fore TAE.
There was no differe nce among the patie nts who unde rgone TAE via PHA, RHA, and AHA.
DISCUSSION Although seve ral studie s of the histopathologica l change s of hepatoce llular carcinoma afte r TAE have bee n reporte d (12± 15) , little is known about change s in the noncance rous hepatic pare nchyma that is damage d by TAE (16 ± 18) . Kobayashi et al (18) e xamine d the histopathologic change s of the portal tract in the vicinity of HCC nodule s 10 days to six months afte r TAE and observe d variable damage to the hepatic artery and portal ve ins caused by anticance r drugs or Lipiodol adde d to Gelfoam emboli. Anticance r drugs are che mical age nts that produce cell injury. Arterial occlusion due to ge latin sponge particle s may also re sult in acute hypoxic damage to the endothe lium. By the se two mechanism , TAE provoke s acute in¯ ammation of the he patic pare nchyma. The acute in¯ ammatory re sponse s are induce d by: (1) vasodilatation, which ® rst involve s the arte riole s and
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TSUSHIMA E T AL
the n results in the ope ning of ne w microvascular beds in the area, causing incre ase d blood ¯ ow; (2) incre ase d vascula r pe rme ability and e xudation of plasma prote ins, the hallmark of acute in¯ ammatory ede ma; and (3) le ukocytic e xudation (19) . It is suspe cted that this vasodilatation contribute s to the transie nt incre ase in arte rial perfusion in the hepatic pare nchyma afte r TAE. In two patie nts, arte rial perfusion was decrease d afte r TAE. In one of the se two patie nts, TAE had bee n performed four time s before this study. The refore , one possible e xplanation is that the decreased arterial pe rfusion after TAE may have bee n due to the inability of the damage d he patic arte rial branche s to furthe r dilate or re canalize . In anothe r patie nt in whom arterial pe rfusion was de crease d, TAE was pe rformed via AHA. This se le ctive embolization may contribute to pre ve nting recanalization of occlude d arterial branche s. Arterioportal shunting can occur in cirrhotic live r without tumor. Obstruction of minor shunting due to TAE, which can not be identi® e d by arteriography, may also decrease arte rial pe rfusion afte r TAE . Howe ve r, quantitatin g the de gre e of shunting is not e asy. Taoure l e t al (7) e valuate d the se rial hemodynamic change s that occur afte r TAE by Dopple r sonography and conclude d that TAE induce d a rapidly re ve rsible de crease in he patic arte rial ¯ ow. In the ir study, howeve r, blood ¯ ow measure ment was performed only two days after TAE. The signi® cant incre ase in arte rial perfusion due to acute in¯ ammatory change s may appe ar afte r this time. In our study, the arte rial perfusion was incre ase d two to six days after TAE in 20 of 22 patie nts. In addition, hepatic arte rial ¯ ow measure d at the le vel of the hepatic artery by Dopple r ultrasonography may not re pre sent arte rial perfusion of the he patic pare nchyma, since retrograde arte rial ¯ ow through collate ral or acce ssory vesse ls may appe ar afte r occlusion of the hepatic arte rie s. Acute in¯ ammatory ede ma incre ase s the pre ssure of the interstitial ¯ uid. In live r cirrhosis, since the inte rconne cting ® brous scars of the live r may pre vent the re le ase of incre ase d pressure , the intrahe patic portal branche s are compre ssed and resistance to portal ¯ ow may be incre ase d, re sulting in decrease d portal pe rfusion in the pare nchyma. This change also means that portal hype rte nsion may occur after TAE. Since Lipiodol de posits may be obse rved not only in HCC but also in the sinusoids of noncance rous live r tissue (16) , Lipiodol de posits in the sinusoids may also contribute to the de crease d portal pe rfusion measure d at the tissue le vel. Howe ver, the incre ase d
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arterial pe rfusion cannot be e xplaine d by this mechanism (20) . In thre e case s, portal pe rfusion two to six days afte r TAE was incre ase d. Hepatic arterial ¯ ow is re gulate d by an intrinsic regulatory syste m, the he patic arte rial buffe r re sponse (20) . The live r is not capable of directly controlling portal ve nous ¯ ow, ie , change s in the he patic arterial perfusion do not alte r portal vascular ¯ ow or resistance (20) . The mechanism of the incre ase in portal perfusion afte r TAE obse rve d in thre e case s is unknown. O ur results disagre e with those of othe r studie s in which the portal ¯ ow was increased (8) or unchange d (7) after TAE. Moriyasu et al (21) reporte d that ne ither portal venous pre ssure nor portal blood ¯ ow showe d any consiste nt trend after TAE. Howeve r, in the se re ports, portal blood ¯ ow was measure d at the le ve l of the portal trunk or right portal vein by Dopple r ultrasonography. Portal ¯ ow measure d at the portal trunk or its branche s doe s not re pre sent portal pe rfusion in the he patic pare nchyma because of the pre sence of the portosyste mic venous shunt, which occasionally appe ars in patie nts with live r cirrhosis. Shimomura et al (22) e valuate d portal hemodynamic change s using iodine -123 scintigraphy and conclude d that blood ¯ ow in the portosyste mic ve nous shunt is signi® cantly incre ase d afte r TAE. The ir re sults sugge st the possibility that portal pe rfusion in the hepatic pare nchym a may be de cre ase d afte r TAE , e ve n though blood ¯ ow measure d at the portal trunk or right portal ve in is unchange d or incre ase d. The methods for quantifying tissue pe rfusion pe r volum e by dynamic CT were described by Mile s and coworke rs (9, 10) , while Blomle y et al (11) reporte d a method of separating and quantifying the two compone nts of live r blood ¯ ow (arte rial and portal) at the tissue leve l. The the ore tical aspe cts of this method have bee n discusse d in de tail in previous pape rs (9 ± 11, 23± 25) . Reliability and re producibility were well studie d in vitro (25) and in vivo (9 ± 11, 23, 24, 26) . This method was used to show that portal perfusion is signi® cantly decrease d in patie nts with live r cirrhosis (10, 11) and has also bee n applie d to the study of blood ¯ ow in the kidne ys, myocardium , and brain (24, 27± 32) . Howe ve r, this technique has se veral limitations. First, only one se ction le ve l can be studie d. This section should include not only the live r and sple e n, but also the portal trunk. The pe rfusion of a solid organ may not be homoge nous. In our study, pe rfusion measure ments were , as far as possible , pe rforme d at the same location be fore and afte r TAE in each patie nt. Second, patie nt movement during the Digestive Diseases and Sciences, Vol. 43, No. 2 (February 1998)
PERFUSION CHANGES DUE TO TAE
single -location se que nce may de grade image quality, resulting in errone ous CT numbe r measure ment. It is important that CT numbe r measure ments of the live r pare nchyma be precise, be cause the CT numbe r increase in the hepatic pare nchyma in its pre portal phase is small. Lipiodol de posits in the he patic parenchyma may also be a source of incorre ct CT number measure ments. In conclusion, the arterial perfusion of the noncancerous hepatic pare nchyma, as measure d by dynamic CT, was transie ntly increased two to six days afte r TAE. This reaction may have be en due to acute in¯ ammatory vasodilatation induce d by anticance r drugs and ge latin sponge particle s. We demonstrate d a de crease in portal perfusion after TAE, which we suspe ct is due to incre ase d tissue pressure of the live r. Quanti® cation of tissue perfusion by dynam ic CT may be use ful for studying he modynamic change s afte r TAE, but our results must be con® rmed by furthe r studie s. REFERENCES 1. Yamada R, Sato M, Kawabata M, Nakatsuka H, Nakamura K, Takashima S: He patic artery e mbolization in 120 patie nts with unre sectable hepatoma. Radiology 148:397± 401, 1983 2. Ohishi H, Uchida H, Yoshimura H, Ohue S, Ueda J, Katsuragi M, Matsuo N, Hosogi Y: He patocellular carcinoma dete cte d by iodized oil: Use of anticance r age nts. Radiology 154:25± 29, 1985 3. Takayasu K, Shima Y, Muramatsu Y, Moriyama N, Yamada T, Makuuchi M, Hase gawa H, Hirohashi S: Hepatocellular carcinoma: Tre atme nt with intra-arterial iodized oil with and without che mothe rape utic agents. Radiology 163:345± 351, 1987 4. Sasaki Y, Imaoka S, Kasugai H, Fujita M, Kawamoto S, Ishiguro S, Kajima J, Ishikawa O, Ohigashi H, Furukawa H: A ne w approach to chemoembolization therapy for hepatoma using e thiodized oil, cisplatin, and ge latin sponge. Cancer 60:1194 ± 1203, 1987 5. Nakamura H, Hashimoto T, Oi H, Sawada S: Transcathe ter oily chemoem bolization of hepatocellular carcinoma. Radiology 170:783± 786, 1989 6. V etter D, Wenger J, Bergie r J, Doffoel M, Bockel R: Transcathe ter oily chemoem bolization in the managemen t of advance d he patoce llular carcinoma in cirrhosis: Re sults of a Western comparative study in 60 patients. He patology 13:427± 433, 1991 7. Taourel P, Dauzat M, Lafortune M, Pradel J, Rossi M, Brue l JM: Hemodynami c change s after transcathete r arte rial e mbolization of he patocellular carcinoma. Radiology 191:189 ± 192, 1994 8. Ohnishi K, Sato S, Tsunoda T, Sugita S, Nomura F, Iida S: Portal ve nous hemodynamics in hepatocellular carcinoma: Effects of hepatic arte ry embolization. Gastroente rology 93:591± 596, 1987 9. Miles KA: Me asurement of tissue pe rfusion by dynamic computed tomography. Br J Radiol 64:409 ± 412, 1991 Digestive Diseases and Sciences, Vol. 43, No. 2 (February 1998)
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